Chemical compound



Patented Apr. 27, 1943 2,217,571 CHEMICAL COMPOUND Oakley Ormer Cook andClaud E. Watson, Dallas, Tex., assignors of one-tenth to Albert L. Reedand Carl B. Callaway, Dallas, Tex.

No Drawing. Application June 6, 1941,

Serial No. 396,938

6 Claims. (01. 260-387) This invention relates to a series of new anduseful chemical compounds produced by combining the metal ion of a metalelement with a dye of the triphenyl-methane series.

This application is a continuation-in-part of our prior application,Serial No. 312,980, filed January 8, 1940, and entitled Bactericide andprocess of making the same, relating to a new product comprising astable solution of triphenyl- "rosaniline, triphenyl-para-rosaniline, orhexamethyl-para-rosaniline combined with an organic salt of copper suchas copper acetate.

The new compounds and substances have low toxicity to body tissues andpossess a high quality 'of stimulating the reticulo-endothelial system,

the principal defense agent of the body against disease. Among othertherapeutic effects these new substances possess a high penetratingefiect on colloids, such as cell protoplasm, egg albumin,micro-organisms, and the wax, such as produced by and surroundingtubercle bacilli.

Other valuable effects of these products on living tissue are theiranaesthetic reaction on nerve tissues and their use as a sclerosingagent in injection treatments. The compounds possess use in killingfungi found in various fungus infections of the body and in thepurification of water,

while their stability and solubility maintenance render them valuable inintravenous injections.

The present invention includes those products formed by combining anorganic or inorganic salt of copper or other metals such as antimony,gold,

silver, zinc, and mercury into stable compounds by reacting the metalion of selected metal salt with a dye of the triphenyl-methane series.The copper salts combined with a triphenyl-methane series dye,particularly the rosaniline derivatives, when reacted in the presence ofa stabilizin agent in the form of an organic acid, produce aprotozoacide of great potency which has been used with remarkablesuccess in treating and controlling malaria.

The lethal action of the compounds produced by the present invention onorganisms in human and animal bodies indicates that difierent metal ionshave selective action upon particular organisms so that one organism maybe eradicated with greater ease with one particular metal ion than byanother ion. For example, arsenic and mercury ions when combined intostable solutions in accordance with the instant invention appear to havegreat affinity for the spirochaetes of syphilis and a less aflinity forthe organisms of malaria and the gonococi have great affinity for thesilver salts.

Fundamentally, this invention includes the preparation of organiccompounds not previously known, said compounds possessing unusualbactericidal, ovacidal, fungicidal, and protozoacidal action whenintroduced on and into living tissue without deleterious effect thereto.

Broadly the invention includes the formation of stable chemicalcompounds by combining dyes or the triphenyl-methane series,particularly a rosaniline dye, with the metal ion of a metal salt ofantimony, gold, silver, zinc, mercury, and copper, particularly theorganic and inorganic copper salts. The metal salt may be the acetate,citrate, lactate, malate, tartrate, salicylate, formate, or sulfate.

In reacting the dye with the metal ion it is preferable to have astabilizing agent present to assist in keeping down precipitation and topreserve the product in storage, a even small amounts of alkali from theglass of the storage containers may be detrimental. Furthermore, astabilizing agent in the form of an organic acid which may be one of thehydroxy-acids or, spe- .cifically, lactic,,acetic, tartaric, or malicacid,

tends to prevent the alkali of the blood from acting too rapidly on thedye-metal molecule before the compound has sufficient time to manifestaction on the serum and cell colloids. This is fundamental and therebycontrol of the splitting off of the metal from its conveyor is obtained.

The stabilizer also determines the hydrogen ion concentration of theproduct, and, although any of the organic acids mentioned is operable,the amounts used are based on the hydrogen ion concentration of lacticacid as a control.

As before stated, the several organic and inorganic salts of the metalsenumerated may be used in preparing the present products, and, whenusing copper salts, the citrate, lactate, malate, tartrate, salicylate,formate, and sulfate forms are applicable. As a criterion, the amountsof these several salts may be proportioned to the relative amount ofcopper contained in each as shown by their molecular weights to supplycopper equivalent to that of 0.04 gm. of copper acetate per c. c. offinished product.

While inorganic salts such as copper sulfate have valuable uses,particularly for external application, the organic salts such as theacetate are preferred for intravenous application.

In making up the dye solution from the selected triphenyl-methane seriesdye, it is preferable to dissolve the dye in a solvent which may be oneof the alcohols such as ethyl, amyl, butyl, propyl, or other higheralcohols or acetone, al-

though for intravenous injection the alcohol are generally recommended.

As before stated, any of the dyes of the triphenyl-methane series may beused to obtain the new products and resultant benefits of thisinvention, particularly the rosaniline dyes and more specificallycrystal violet, methyl violet B, and gentian violet. As illustrative ofone detailed example of a manner of preparing one type of compoundincluded within the broad invention, those skilled in the art arereferred to the following:

Starting with crystal violet which is a pararosaniline derivative or,more particularly, a mixture of the hydrochlorides ofpentamethylpara-rosaniline and hexamethyl-para-rosaniline, a solution isprepared of approximately 1.5 grams of the compound dissolved inapproximately 10.526 0. c. of alcohol (U. S. P.) and approximately 90 o.c. of water.

A solution of cupric acetate is then prepared which is composed ofapproximately 0.4 to 0.5 gram of the acetate dissolved in approximately90 c. c. of water-to which is added approximately 1.136 to 2 c. c. oflactic acid (85%) (U. S. P.) with'sufiicient water to make up 100 c. c.of solution. Thereafter approximately 8 c. c. of the copper saltsolution are mixed with'90 c. c. of dye solution and the mixture isdiluted to make up a unit of 100 c. 0.

After allowing the mixture to stand for approximately 24 hours, it ispassed under vacuum through a Berkfeld filter into a closed container.The solution is then in condition for immediate use or it may be storedand dispensed in serum bottles or ampules. It will also be understoodthat, if desired, the solution may be evaporated under proper conditionsto form a dry crystalline powder.

What we claim is:

1. As a therapeutic product, a dye selected from the group consisting oftriphenyl-rosaniline, triphenyl-para-rosaniline andhexamethyl-pararosaniline chemically combined with the metal ion of ametal selected from the group consisting of copper, antimony, gold,silver, zinc and mercury and stabilized by an organic acid selected fromthe group consisting of lactic, tartaric, malic and acetic acids.

2. As a therapeutic product, a rosaniline dye dissolved in a solventselected from the group consisting of ethyl, amyl, butyl and propylalcohols and chemically combined with a metal salt, the solution beingstabilized with an hydroxyl aliphatic acid.

3. As a non-toxic, stable therapeutic product, crystal violet dyedissolved in an alcohol and chemically combined With an organic metalsalt, the product being stabilized with lactic acid.

4. As a new therapeutic product, the compound resulting from thecombination of a rosaniline dye selected from the group consisting ofcrystal violet, methyl violet B and gentian violet dis solved in asolvent therefor and chemically combined with an organic copper saltselected from the group consisting of copper acetate, citrate, lactate,malate, tartrate, salicylate and formate and in the presence of astabilizing agent selected from the group consisting of lactic,tartaric, malic and acetic acid.

5. A therapeutic composition produced by admixing a solution ofrosaniline with a solution oi. copper acetate and comprising thereaction prodnot of rosaniline and copper acetate in the approximatemolecular ratio of 3.4 parts of rosaniline to .01 part of copperacetate.

6. A stable therapeutic composition of low toxicity possessingsubstantial protozoacidal power comprising the reaction productresulting from chemically combining a mixture of the hydrochlorides ofpentamethyl-para-rosaniline and hexamethyl-para-rosaniline and anorganic salt of copper and wherein the relative amount of copper presentis substantially equivalent to 0.04 gm. per 100 .cc. when copper acetateis used as the organic salt of copper. 1

OAKLEY ORMER COOK. CLAUD E. WATSON.

